Immediate and short-term effects of eccentric muscle contractions on structural, morphological, mechanical, functional and physiological properties of peripheral nerves: A protocol for a systematic review and meta-analysis

Background It is widely acknowledged that eccentric muscle contractions may cause skeletal muscle damage. However, there is little knowledge about the impact of eccentric contractions on non-muscular structures. Animal and human studies revealed that eccentric contractions can also induce immediate and short-term nerve dysfunction. The purpose of this review is to examine whether eccentric muscle contractions induce immediate and short-term effects on structural, morphological, mechanical, functional and physiological properties of peripheral nerves, from both animal and human studies. Methods and analysis A systematic review of randomised (RCTs) and non-randomised controlled trials will be conducted. Four electronic databases (i.e., Medline/Pubmed, Science Direct, PEDro and Cochrane) will be searched using predefined search terms to identify relevant studies. Eligible studies have to comprise any type of eccentric contraction of upper or lower limb muscles. Primary outcomes will include measures related to structure, morphology, mechanical, functional and physiological properties of peripheral nerves. Two independent reviewers will assess eligibility, evaluate risk of bias, and extract relevant data. In human studies, the risk of bias will be assessed by the Cochrane Collaboration risk of bias tool (RoB 2.0 tool) for RCTs and by risk of bias in non-randomised studies of interventions (ROBINS-I) for non-randomised controlled trials; while for animal studies, the risk of bias will be assessed using the SYRCLE’s RoB tool. A narrative synthesis will be conducted for all included studies. Also, if appropriate, a meta-analysis will be performed, where the effect size of each outcome will be determined by the standardized mean difference as well as the 95% confidence intervals. I2 statistics will be used to assess heterogeneity. Ethics and dissemination For this study, no ethical approval is required. Findings will be disseminated widely through peer-reviewed publication and conference presentations. Systematic review registration The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO). Registration number: CRD42021285767.

"These changes could potentially explain the loss of strength observed after eccentric or unaccustomed exercise." "Also, temporary strength loss was present which gradually recovered over time; suggesting that a potential link may exist between the effects of nerve properties and the strength loss.." "These changes were accompanied by progressive decrease in plantar flexors torque across the bouts. Therefore, consecutive bouts of eccentric contractions with fast angular velocity cause severe nerve properties alterations, and thus impairing skeletal muscle function." Comment 2: For disruption of peripheral nerves to occur, is it necessary to perform specific eccentric contraction (like isokinetic contractions) or does it also occur when performing functional daily living movements or strength exercises?
Response: It is not to be expected that, in healthy people, nerve damage will occur, and the properties of the nerves will change as a result of performing functional daily living activities, unless a considerable muscular contraction intensity and volume (i.e., repetitions) are associated with those activities.
Comment 3: I might have missed it, but are these alteration transient? How many days (or hours) does it last? When observed, is the person more susceptible to injury?
Response: From our preliminary search, we assume these alterations are transient and there is a potential time course difference between animal and human studies. However, after the validation of the protocol, we hope to obtain answers and conclusions about the question raised. Nevertheless, we added information to the cited studies about the time course of the nerve effects. Please consider the changes in lines # 80-83 and 92-94. The revised text reads as follows: "The damage to the myelin sheath caused transient sciatic nerve dysfunction, manifested by a significant decline (i.e., -21%) in nerve conduction velocity (NCV) observed on day 7 after eccentric contractions, which returned to baseline values on day 10. 14 " "Consistent with these animal studies findings, it has been shown that eccentric contractions induce a temporary reduction on nerve function in healthy individuals. 16-19 " Comment 4: As described by the authors, it seems that the peripheral nerve alterations observed after eccentric exercise are somewhat similar those of exercise induced muscle damage. If this is the case, are both things liked? And if so, I would suggest to bring it up.
These comments are made thinking that this is a topic that is not widely discussed so many readers might be reading it for the first time. Addressing possible functional alterations as well as wider possibilities to induce peripheral disruption might strengthen the rationale to and the necessity to study this topic.
Response: Please note that eccentric exercise with sufficient dose (i.e. both intensity and volume) is suggestive of inducing muscle damage. We assume that, beside the muscle, the nerve is also affected. In the first paragraph we clarify this potential link; and, following your suggestion, we have now improved the introduction to transmit this rationale.

Comment 5: 2.1.1 Type of studies and 2.1.2 Types of participants
Does the inclusion of studies "evaluating the impact of eccentric contractions (applied to upper or lower limb muscles) on peripheral nerves dysfunction…", isn't it possible that the inclusion of individual with peripheral nerves dysfunction will interfere in the results when compared to health tissues? Also, in the following topic "2.1.2 Types of participants" it is specified that will be included studies with "healthy asymptomatic individuals", isn't it contradictory? I might be missing a point here.
Response: Thank you for highlighting this inconsistency. When describing the type of studies, where we wrote "studies evaluating the impact of eccentric contractions (applied to upper or lower limb muscles) on peripheral nerves dysfunction", we meant to say that studies would be included if they evaluated alterations in different peripheral nerve properties. Thus, "dysfunction" was used to mean the different nerve damage markers that we described afterwards. However, we recognize that it may induce some bias in the way the information is interpreted. Please consider the changes in lines # 121-124, as the revised text reads as follows: "The review will include randomised (RCTs) and non-randomised controlled trials or quasi-experimental studies evaluating the effects of eccentric contractions (applied to upper or lower limb muscles) on peripheral nerves structural, morphological, mechanical, functional and physiological properties." Comment 6: Why are the following outcomes included:? 4. Physiology: intraneural blood flow measured with Doppler US (B-mode with Colour Doppler)… alterations in signal intensity (T1 and T2 via MRI) and echo intensity (via high-resolution US)

Response:
We have decided to include these outcomes because changes at these levels could be associated with alterations in peripheral nerve physiology and could be considered as nerve damage markers. For instance, increased intraneural blood flow could be attributed to neuronal inflammation that results in activated inflammatory cytokines, induction of nitric oxide synthase and increased vasodilation. Increased intraneural blood flow and changes in signal intensity (T1 and T2 via MRI) and echo intensity (via highresolution US) were observed in clinical population. Please consider below some references to support the aforementioned justification.

References:
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